Abstract West Nile virus (WNV) is an emerging infectious disease of public health importance. In humans, WNV can cause a life threatening illness and damage to the central nervous system (CNS). We have linked WNV infection outcome with the regulation of host cell pathogen recognition receptor (PRR) signaling programs of innate immunity that trigger interferon alpha/beta expression and that activate interferon regulatory factors (IRFs) to induce antiviral response genes that control infection. We now propose to determine the specific PRRs, IRFs, and their intracellular signaling pathways that control cell-specific imimune defenses and the outcome of WNV infection. Our studies will 1) Determine the effect of specific PRR and IRF genes on cell tropism of WNV infection, and 2) Define the PRRs and IRFs that serve to control CNS entry and pathogenesis of WNV infection. These studies will reveal the host innate immune signaling and response features that control WNV infection.